The long-term objective of this proposal is to understand how tolerance versus immunity is regulated during microbial infection. The research proposed uses mouse infection with the protozoan parasite Toxoplasma gondii, a Th1-inducing pathogen, to probe regulation of immunity locally and during disseminated infection. Intracellular signaling along a Wnt/?-catenin pathway is emerging as an important regulatory axis in the immune system. Activation of this pathway in dendritic cells promotes tolerance in the intestinal mucosa. Using transgenic mice possessing dendritic cell-specific ?-catenin deletion and mice in which dendritic cell ?-catenin is constitutively active, we will determine how dendritic cell ?-catenin signaling impacts inflammation and immunity during Toxoplasma infection. The central hypothesis of the proposal is that Wnt/?-catenin signaling promotes a tolerogenic phenotype in DC that limits immune-mediated damage Toxoplasma infection, but that also places limits on the ability to generate protective T cell-mediated immunity. The hypothesis will be tested using two specific aims. Aim 1 : Determine the function of dendritic cell Wnt/?-catenin in intrinsic cytokine and signaling responses and in ability to stimulate antigen specific T cell responses. We will establish how Wnt/?-catenin signaling impacts other immunity-related signaling pathways in dendritic cells, and in turn how this affects T subset differentiation. Aim 2 : Understand how DC Wnt/?-catenin signaling impacts inflammation and immunity during in vivo infection. We will determine the impact of Wnt/?-catenin signaling on Toxoplasma-induced inflammation in the intestinal mucosa, and we will determine how the role of this pathway in emergence of T cell immunity during in vivo infection. The importance of the research is that the data generated by following these specific aims will deepen our understanding of regulation of immunity and inflammation during infection, in particular as related to Wnt/?- catenin signaling which is poorly understood at present. The ultimate impact of the research is that it can be expected to ultimately identify novel targets for immunotherapy in inflammatory disease, as well as providing new targets to promote immunity during infectious disease.

Public Health Relevance

of the project to public health is that it deals with host immune responses and inflammation during Toxoplasma gondii infection. This parasite is classified as a class B biodefense pathogen. Toxoplasma is a common opportunistic infection in humans that can cause life-threatening disease in immunocompromised populations and in congenital infection. Completing the project may ultimately identify new targets to treat inflammatory disease in the intestinal mucosa and to improve immunity to microbial infection.